The hepatitis C viruses (HCV) are small RNA viruses within the family Flaviviridae, distinguished from other members by their capacity to cause persistent infection in humans with serious consequences such as chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. The mechanisms by which HCV established that the HCV major envelope glycoprotein E2 interacts with the cell surface molecule CD81, which may serve as a virus receptor. CD81 is expressed on many different human cell types, including B lymphocytes, where it is known to associate with other molecules including CD19, MHC Class II antigen, lymphocytes, where it is known to associate with other molecules including CD19, MHC Class II antigen, and the C3 receptor. CD81 participates in several functional activities of B cells, including aggregation, adhesion, and antigen- receptor-mediated activation. B cell abnormalities have been associated with chronic HCV infection, including polyclonal activation with or without cryoglobulinemia, several other dyscrasias, and some rare lymphomas. In addition, the propensity for delayed seroconversion during acute HCV infection and the emergence of antibody-escape mutants during the chronic phase of disease raises the question of whether fundamental disturbances in normal B cell function occur as a consequence of either their infection with virus or chronic exposed to E2 glycoproteins on circulating virus. Although it has not been established that antibody responses to HCV are important correlates of protein against persistent infection, defective B cell function and impaired humoral immunity could contribute to inefficient clearance of virus in some cases, particular if other factors such as cytotoxic T cell responses are weak. We propose to investigate the hypothesis that interaction of E2 with CD81 on the plasma membrane of B lymphocytes and/or within intracellular compartments, leads to alterations in the properties of this multi-functional ell surface protein that in turn compartments, leads to alterations in the properties of this multi-functional cell surface protein that in turn affect the capacity of B ell s to respond normally to viral antigens. Such alterations could include higher thresholds for activation, reduced antigen presenting capacity and/or defective complement regulation. Using model systems, and clinical specimens of HCV-infected individuals, we specifically will: 1) Investigate whether chronic infection with HCV is associated with disturbances in B cell function, such as reduced level of CD81 expression, impaired responsiveness to antigen, and other in vitro measures of activation; 2) Determiner whether exogenous E2 interacts with CD81 on B cell lines and whether such interaction leads to alterations in CD81-associated events; 3) Determine whether E2 interacts with CD81 during intracellular synthesis and processing in B cells, and whether there are functional consequences for cell surface CD81 expression and function.